Individual differences in drug abuse vulnerabilities among humans display genetic as well as environmental components. During this year, these investigators continued to explore roles of allelic variants at gene loci in contributing to human individual differences in drug abuse vulnerability and in individual differences in related phenotypes. We reported that individual differences in rate at which use of addictive substances is taken up during adolescence could be indentified for alcohol, tobacco smoking and cannabis smoking using a latent class approach. Individual differences in probabilities of membership of these classes were strongly associated with individual differences in a quit success genotype score, linking (for the first time) genetic influences on uptake of addictive substance use with those on abilities to quit (smoking, at least) . Subsequent to publication of this data, we were ale to identify trajectories for uptake of use of tobacco and cannabis smoking that also display influences of the quit success v1.0 genotype score, though no such association was noted for uptake of alcohol use. Several chromosomal regions previously nominnated by our studies have been replicated in datasets from other laboratories that became available during this year. Fine mapping studies have identified particular haplotypes at several gene loci that represent the strongest candidates for addiction vulnerability genes in humans. These studies point toward a role for individual differences in brain structures, as well as functions, in vulnerability to addictions and especial roles for genes encoding molecules that participate in cell adhesion mechanisms. These human data for the most strongly supported genes are now supported by results from studies in mouse models (see other annual reports) Based on data from CDH13 knockout mice, we formulated specific hypotheses that on task measures would correlate with CDH13 variation in humans. This hypotheses was supported by data from developmentally-assessed humans. We developed a composite measure of environmental influences during this year,based on assessments of items that vary in family environment (parental monitoring) and those that vary in the unique environment (peer use). This composite environmental factor displayed significant interaction with influences of our previously-studied v1.0 quit success polygenic score in helping to determine which individuals went on to greater use of tobacco and of cannabis. We also identified, for the first time, significant interactions between an interventions' success in prevention of substance use and a polygenic score that predicts rate of uptake of substance in all individuals.